Controlled release methodologies may be conveniently classified as, diffusion controlled, solvent controlled or chemically controlled, depending upon the mechanism that controls the release of the therapeutic agent.
It is possible to utilize diffusion controlled or solvent controlled devices for the controlled release of macromolecules. However, such devices are nonerodible, so that systemic drug delivery from an implant site requires, first surgical implantation and then subsequent surgical removal of the expended device.
Attempts have been made to dispense therapeutic macromolecules from hydrogels. Because the bioerosion rate of the prior art hydrogels (such as hydrogels prepared by copolymerisation of N,N'-methylene-bisacrylamide and various water-soluble monomers) is extremely slow, there has been very poor control over the rate of therapeutic macromolecule delivery. Thus, as shown by the work of Torchilin et al. described in J. Biomed. Mater. Res., 11, 223-231 (1977), only hydrogels containing less than 1 weight percent crosslinker are bioerodible. Macromolecule release from such loosely crosslinked hydrogels occurs largely, if not solely, by diffusion, and almost 50% of the entrapped macromolecule is released in the first day of utilization.
In a recent patent (U.S. Pat. No. 4,502,976) Heller described a polyester hydrogel which represents a substantial improvement over the work reported by Torchilin et al. Heller states that the erosion rate and the concommitant release of incorporated macromolecules could be manipulated by simple changes in the chemical structure of the hydrogel.
Polycetals have been prepared by the condensation of polyols with carbonyl compounds, or by the self condensation of carbonyl compounds. N. G. Gaylord "Encyclopedia of Polymer Science and Technology, Interscience, N.Y. 1969 Vol. 10, p. 319.
Polyacetals have also been prepared by the reaction of divinyl ethers and polyols. Heller et al. J. Polymer Sci., Polymer Letters Ed. 18, 293 (1980).
French Patent No. 2,336,936, refers to crosslinked polyacetals formed by the condensation of diols or polyols with 3,4-dihydro-2H-pyran-2-ylmethyl-3,4-dihydro-2H-pyran-2-ylcarboxylate.
In a copending application Ser. No. 892,520 filed 8/1/86, now U.S. Pat. No. 4,713,441 Heller et al describes the preparation of polyacetal hydrogels from divinyl ethers and polyols.
However, the prior art is silent as to the preparation of polyacetal or polyketal from acetals of ketals and polyols hydrogels that can be subsequently crosslinked under mild conditions to entrap macromolecular therapeutic agents. These agents may then be released in a controlled manner as the hydrogel bioerodes.